alpha(2)-Adrenergic receptors play an essential role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the CNS. However, the role of each of the three highly homologous alpha(2)-adrenergic receptor subtypes (alpha(2A), alpha(2B), alpha(2C)) in this process has not been determined unequivocally. To address this question, the regulation of norepinephrine and dopamine release was studied in mice carrying deletions in the genes encoding the three alpha(2)-adrenergic receptor subtypes. Autoradiography and radioligand binding studies showed that alpha(2)-receptor density in alpha(2A)-deficient brains was decreased to 9 +/- 1% of the respective wild-type value, whereas alpha(2)-receptor levels were reduced to 83 +/- 4% in alpha(2C)-deficient mice. These results indicate that approximately 90% of mouse brain alpha(2)-receptors belong to the alpha(2A) subtype and 10% are alpha(2C)-receptors. In isolated brain cortex slices from wild-type mice a non-subtype-selective alpha(2)-receptor agonist inhibited release of [(3)H]norepinephrine by maximally 96%. Similarly, release of [(3)H]dopamine from isolated basal ganglion slices was inhibited by 76% by an alpha(2)-receptor agonist. In alpha(2A)-receptor-deficient mice, the inhibitory effect of the alpha(2)-receptor agonist on norepinephrine and dopamine release was significantly reduced but not abolished. Only in tissues from mice lacking both alpha(2A)- and alpha(2C)-receptors was no alpha(2)-receptor agonist effect on transmitter release observed. The time course of onset of presynaptic inhibition of norepinephrine release was much faster for the alpha(2A)-receptor than for the alpha(2C)-subtype. After prolonged stimulation with norepinephrine, presynaptic alpha(2C)-adrenergic receptors were desensitized. From these data we suggest that two functionally distinct alpha(2)-adrenergic receptor subtypes, alpha(2A) and alpha(2C), operate as presynaptic inhibitory receptors regulating neurotransmitter release in the mouse CNS.
Together these data imply that nmDC phenotypical differ from omDC which might result in diverse functional properties and might be of relevance for selecting routes for immunotherapy of atopic diseases. Moreover these data provide a basis for further studies investigating immunological mechanisms underlying mucosal immunotherapy.
Although G protein-coupled receptor-mediated signaling is one of the best studied biological events, little is known about the kinetics of these processes in intact cells. Experiments with neurons from ␣ 2A -adrenergic receptor knockout mice suggested that the ␣ 2A -receptor subtype inhibits neurotransmitter release with higher speed and at higher action potential frequencies than the ␣ 2C -adrenergic receptor. Here we investigated whether these functional differences between presynaptic ␣ 2 -adrenergic receptor subtypes are the result of distinct signal transduction kinetics of these two receptors and their coupling to G proteins. ␣ 2A -and ␣ 2C -receptors were stably expressed in HEK293 cells at moderate (ϳ2 pmol/mg) or high (17-24 pmol/mg) levels. Activation of G protein-activated inwardly rectifying K ؉ (GIRK) channels was similar in extent and kinetics for ␣ 2A -and ␣ 2C -receptors at both expression levels. However, the two receptors differed significantly in their deactivation kinetics after removal of the agonist norepinephrine. ␣ 2C -Receptor-activated GIRK currents returned much more slowly to base line than did ␣ 2A -stimulated currents. This observation correlated with a higher affinity of norepinephrine at the murine ␣ 2C -than at the ␣ 2A -receptor subtype and may explain why ␣ 2C -adrenergic receptors are especially suited to control sympathetic neurotransmission at low action potential frequencies in contrast to the ␣ 2A -receptor subtype. G protein-coupled receptors (GPCRs)1 transfer a large diversity of extracellular signals into the cell interior, including light, neurotransmitters, and hormones. Although GPCRs represent some of the best studied signaling molecules, relatively little information exists about the kinetics of signal transduction by these receptors (except for rhodopsin) in intact cells. However, more detailed knowledge about the kinetic properties of GPCR signal transduction would be of particular interest to determine the physiological significance of closely related receptor subtypes, which can be activated by the same endogenous agonist but differ in their biological function.Functional data on ␣ 2 -adrenergic receptor subtypes suggest that they differ in their signaling kinetics. Interestingly, several physiological differences were identified between presynaptic ␣ 2A -and ␣ 2C -receptor subtypes (1). In mouse atria, the ␣ 2A -subtype inhibited norepinephrine release at high stimulation frequencies whereas the ␣ 2C -receptor operated at lower levels of sympathetic nerve activity (1). Moreover, inhibition of norepinephrine release mediated by the ␣ 2A -subtype occurred much faster than inhibition by the ␣ 2C -receptor. These findings indicate that two presynaptic receptors in the inhibitory feedback loop of transmitter release may differentially regulate synaptic transmission. Several explanations may account for these functional differences. ␣ 2 -Adrenergic receptor subtypes have been shown to differ in their signal transduction, agonistdependent internalization and receptor...
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